Current knowledge suggests that the function of the cerebral cortex depends in large part on synaptic interactions between its constituent cells, and so to understand how the cortex functions, it is first necessary to identify its constituent neurons and to determine the numbers and types of synapses linking them with each other and with neurons in other parts of the brain. The local circuits which connect cortical neurons with each other are undoubtedly deeply involved in the "higher" functions of the cerebral cortex. Thus an important aim of the proposed studies is to elucidate intrinsic cortical circuitry by examining the local axonal projectionsof identified neurons. Studies of intrinsic connections will focus on the axon collaterals of projection cells labeled by the retrograde transport of horseradish peroxidase and on the local ramifications of "intrinsic" cells labeled by Golgi or immunohistochemical methods. The second part of the proposed studies concerns the identification and quantification of synapses made by labeled thalamocortical and corticocortical axon terminals with identified neurons in mouse primary somatosensory cortex. Presynaptic elements will be labeled by lesion induced degeneration, which in this system allows thalamocortical and corticocortical synapses to be identified and quantified, or by immunohistochemical methods. Neurons postsynaptic to these afferents will be identified by (1) the Golgi-EM/gold toning method, (2) the retrograde filling of neurons with horseradish peroxidase, (3) by immunohistochemical identification of cellular components (4) or, for some non-spiny neurons, by tracing them in serial thin sections. Serial thin sections will be examined in all phases of the proposed studies because this is the only method by which all the synaptic relationships of one portion of an axon or dendrite can be conclusively demonstrated, enabling both the type and frequency of synapses to be determined. This information is a necessity for the elaboration of accurate theoretical models of cerebral cortical function. In the mouse sensory cortex, neuronal types typical of mammalian cerebral cortex are organized into functional columns similar to those observed in many regions of the subprimate and primate neocortex. For this reason, the proposed studies are expected to uncover principles of cortical functional organization which may be generalized to other cortical systems in other species, including man.